Biomarkers and Coagulation Tests for Assessing the Biosimilarity of a Generic Low‐Molecular‐Weight Heparin: Results of a Study in Healthy Subjects With Enoxaparin

Abstract

Low-molecular-weight heparins (LMWHs) differ considerably in their influence on clotting tests and release of tissue factor pathway inhibitor (TFPI). Biosimilarity therefore becomes an issue when generic forms of LMWHs are developed. So far, no bioequivalence study with a generic LMWH has been reported. A generic enoxaparin (test) was compared with the originator (reference) in 20 volunteers after single-dose subcutaneous administration (40 mg enoxaparin sodium, 4000 IU/mL anti-factor Xa (anti-FXa; activity). Target variables were anti-FXa and anti-FIIa activity, activated partial thromboplastin time (aPTT), prothrombinase-induced clotting time (PiCT), and TFPI over 24 hours. The statistical evaluation of the anti-FXa activity profile demonstrated bioequivalence of test and reference with confidence intervals of area under the plasma concentration-time curve (AUC0-tlast) (93%-99%) and Amax (88%-95%). Confidence intervals of AUC(0-tlast) (89%-102%) and Amax (90%-103%) of anti-FIIa activity also fulfill bioequivalence criteria. The 90% confidence interval for the maximum concentration of TFPI ranged from 90% to 113%. The claim of similarity was also supported by aPTT and PiCT profiles. Bioequivalence with the originator enoxaparin could be demonstrated by ex vivo inhibition of FXa and FIIa activity, by coagulation tests (aPTT and PiCT), and by in vivo release of TFPI. Whether such data also prove biosimilarity of the generic enoxaparin needs to be determined.

Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary

“…Most are Phase I cross over studies in healthy volunteers, with subcutaneous single doses of 100, 400 and 600 mg enoxaparin or comparator. The general conclusions from these studies is that they are bioequivalent . One study has the focus on immunogenicity of a product from Brazil compared to the originator enoxaparin.…”

“…The is that they are bioequivalent. [25][26][27] One study has the focus on immunogenicity of a product from Brazil compared to the originator enoxaparin. There was a difference in AHPF4 antibodies for the biosimilar, but the authors made no conclusions what should be the consequence of this finding.…”

Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes

“…One in vitro study found structural variability but similar biological activities between brand and generic versions [27]. The remaining studies found that bioequivalence was met for the generic version [28][29][30].…”

Low‐molecular‐weight heparin biosimilars: potential implications for clinical practice

“…LMWH have a characteristic molecular weight profile and biological activity in terms of anti‐FXa and anti‐FIIa potency, but cannot be physically detected in vivo as a single chemical entity . Instead, the pharmacokinetic (PK) properties of LMWH, including bioavailability, absorption and elimination, are determined using pharmacodynamic (PD) surrogate markers, such as circulating anti‐FXa and anti‐FIIa activity . Other PD tests, including the ratio of anti‐FXa to anti‐FIIa activity, and assays for tissue factor pathway inhibitor (TFPI), are indirect measures of the in vivo activity of LMWH .…”

“…Instead, the pharmacokinetic (PK) properties of LMWH, including bioavailability, absorption and elimination, are determined using pharmacodynamic (PD) surrogate markers, such as circulating anti‐FXa and anti‐FIIa activity . Other PD tests, including the ratio of anti‐FXa to anti‐FIIa activity, and assays for tissue factor pathway inhibitor (TFPI), are indirect measures of the in vivo activity of LMWH . These measurements are directly influenced by the amount of LMWH present in the plasma sample, although they may not necessarily reflect its full biological activity in vivo , or accurately reflect its clinical efficacy …”